As is known in the art, magnetic resonance imaging (MRI) (also referred to as nuclear magnetic resonance or NMR) and other non-invasive techniques such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), electroencephgraphy (EEG), magnetoencephalography (MEG), positron emission tomography (PET), optical imaging (OR), single photon emission computer tomography (SPECT), functional computerized tomography (fCT) have been proposed to be able to directly examine a combination of brain (cortical and subcortical), brainstem and spinal cord regions in humans for the evaluation of acute and chronic pain states, analgesic responses, therapies including pharmacological or gene products, and placebo responses.
To date, this goal has not been accomplished. The major hurdle to this proposed goal has been the inability to define an objective set of indices that characterize the pain state, its progression over time and its alteration through intervention.
Pain is a complex response that has been functionally categorized into sensory, adaptive, and affective components. The sensory aspect includes information about stimulus location and intensity while the adaptive component may be considered to be the activation of endogenous pain modulation and motor planning for escape responses. The affective component appears to include evaluation of pain unpleasantness and stimulus threat as well as negative emotions triggered by memory and context of the painful stimulus. Extensive electrophysiological research in animals has defined likely neuroanatomical substrates for some of the sensory attributes of pain, such as localization and intensity, and some of the adaptive responses, such as descending analgesia. Other regions activated by painful stimuli have also been identified which may be involved in the affective response, however the neural substrates for the motivational and emotional response to pain remain a topic of debate.
Ronald Melzack and Kenneth Casey state “To consider only the sensory features of pain, and ignore its motivational and affective properties, is to look at only part of the problem, not even the most important part at that”. In Donald Price's treatise on the Psychology of Pain, he defines pain as a somatic perception containing: (1) a bodily sensation with qualities like those reported during tissue-damaging stimulation; (2) an experienced threat associated with this sensation and (3) a feeling of unpleasantness or other negative emotion based on this experienced threat.
To date, although there are clear affective, motivational and emotional components of pain that can be evaluated subjectively, a clear delineation of the neural circuitry involved in the motivational and emotional aspects of pain are only beginning to be evaluated in animal models. A typical current formulation of CNS systems involved in the evaluation of pain intensity (algosity) and unpleasantness (“classic pain circuitry”) is presented in “Pain An Unpleasant Topic,” Pain 1999 Suppl. 6 §61-69, H. L. Fields.
Despite hypotheses about what was constitutes “classic pain circuitry”, the issue of which brain regions process sensory information vs. those that mediate affective responses remains an area of active discussion. Indeed, it is unclear whether unpleasantness is a sensation or an emotion. Another approach for determining which neuroanatomical regions mediate emotional processes regarding pain stimuli might focus on those regions known to be active for motivational processes which underlie emotion. When animals organize behavior in response to aversive or rewarding stimuli, they respond to multiple informational dimensions of these goal-objects or events. These informational dimensions include rate, delay, incidence, intensity and amount and location of the stimulus. A number of brain regions have been consistently implicated in the organization of responses to aversive and rewarding stimuli in animals. More recently, these regions have been specifically implicated in reward processes in humans. These regions, which include the nucleus accumbens (NAc), the sublenticular extended amygdala of the basal forebrain (SLEA), the amygdala, the ventral tegmentum (VT) and the orbital gyrus (GOb), have been shown to be activated in studies of drug-associated reward, in general, these regions are thought to be important for information processing in the service of emotional and motivational states. Traditionally, these regions have been considered in the domain of rewarding rather than aversive stimuli, though, it has been previously postulated that pain and reward are at opposite ends of the same behavioral spectrum.
Motivational states (including aversive states such as pain) which lead to goal-directed behavior depend on a complex informatics system comprised of a set of subprocesses for the moment-by-moment modulation of behavior. The informatics subprocesses can be grouped into three general categories for (1) perceptual processing of goal-objects and other putative rewards, (2) valuation of goal-object worth, and (3) approximation of temporal information and conditional probabilities about the potential reward. The amygdala appears to be a central component of the brain circuitry mediating the first informatics subprocess, while other regions such as the sublenticular extended amygdala (SLEA) of the basal forebrain, and the nucleus accumbens (NAc) appear to be central to the second and third subprocesses respectively. In regard to reward function, input from the dopaminergic neurons of the ventral tegmentum (VT) to the amygdala, SLEA, and NAc is an important feature of this extended system. To date objective indices of function in these regions have not been directly connected to the perception, evaluation, and integration of painful stimuli.
Recent neuroimaging studies have sought to define the principal CNS structures involved in the perception, evaluation and integration of painful stimuli. These studies have contributed to our understanding of the complex nature of the CNS response to pain but have not clearly separated circuitry involved in reward/aversion and emotion from circuitry involved with sensory processing. Direct interrogation of any brain circuitry to objectively define the pain state has hithertofore not been accomplished.
One means for evaluating the brain circuitry mediating acute and chronic pain involves “invasive” approaches. These approaches, have been predominantly restricted to animal research and methods such as placing electrodes into the brain of an animal for electrical recordings, or sacrificing the animal to collect brain tissue for cell culture, immunohistochemistry or other molecular biological techniques.
It would, be desirable to provide a technique and system to non-invasively interrogate the brain of an individual human/animal regarding acute and chronic pain. It would be further desirable to be able to objectively assess pain in humans or animals, or the effects of therapeutic interventions on acute and chronic pain.